The striking discrepancy in the number of end-stage renal disease patients added to the transplant wait list and the shortage of standard criteria donors has stimulated the development of strategies aimed to expand acceptance criteria from marginal deceased donors. Renal biopsy done before transplant will be useful to predict short- and long-term outcomes of kidney transplantation. It also serves as a reference in interpretation of subsequent biopsies. It also helps in deciding whether it should be discarded. However, systemic reviews concluded that there was no consistent association between donor biopsy findings and posttransplant outcomes. A well-designed randomized control trial could ascertain the extent of procurement biopsy leading to discards, whether outcomes are indeed better when preimplantation biopsies are used to justify declining kidneys for transplantation.

Each year, the number of patients with chronic kidney disease is increasing and the patients progressing to end-stage renal disease (ESRD) is on the rise. The ideal treatment for this is renal transplantation. When kidney transplantation is done for these patients, they experience increased life expectancy and better quality of life. The striking discrepancy in the number of ESRD patients added to the transplant wait list and the shortage of standard criteria donors (SCDs) has stimulated the development of strategies aimed to expand acceptance criteria from marginal deceased donors.

Extended criteria donors (ECDs) are donors with age more than 60 years and individuals of 50–59 years with either hypertension, serum creatinine >1.5 mg/dl, or death from cerebrovascular accident. The risk of graft failure after an ECD transplantation is 70% higher than transplant done with SCD.[1]

The donation after brain death (DBD) donor refers to a deceased donor who had primarily brain death in whom cardiac circulation and respiration remains intact or maintained by supportive measures such as mechanical ventilation, drugs, intra-aortic balloon pump, or extracorporeal membrane oxygenation.

The donation after cardiac death (DCD) donor is defined as the donor who does not fulfill the criteria for brain death, and there is no cardiac activity occurred before the organs were procured.

A useful statistic that can be given to transplant candidates is that the projected average added life years after an SCD kidney transplantation is 10 years compared with 5.1 years for an ECD kidney transplantation.[2] Analysis of clinical outcomes from the US national data by Gagandeep et al.[3] showed that both the allograft and the recipient survivals are similar between DCD and DBD, but the risk for delayed graft function (DGF) was 42%–51% in DCD compared with 24% in DBD kidney transplant recipients. Doshi and Hunsicker[4] found no significant difference in the 5-year patient (DCD vs. DBD: 81.3% vs. 81.8%; P = 0.70) and allograft survival (DCD vs. DBD: 66.9% vs. 66.5%; P = 0.52) when comparing DCD with DBD kidney transplantation, but there was a significantly higher risk for DGF with DCD kidney transplantation (DCD vs. DBD: 41% vs. 24%; P = 0.001).

Pretransplant Biopsies

Renal biopsy done before transplant will be useful to predict short- and long-term outcomes of kidney transplantation. It also serves as a reference in interpretation of subsequent biopsies. It also helps in deciding whether it should be discarded.

There has been growing interest in studies to assess the quality of kidneys. The Munster[5] transplant team followed functional kidney weight as kidney weight multiplied by fraction of nonsclerosed glomeruli in preimplantation biopsies. Gaber et al.[6] in 1995 reported that biopsies showing more than 20% glomerulosclerosis on biopsy were associated with reduced graft survival. This study provided the basis for obtaining kidney biopsies at the time of procurement and deciding the kidneys ideal for transplant. Machine perfusion characteristics such as flow rate and renal resistance[7] may also be used to select kidneys for transplantation. Renal damage in pretransplant donor biopsy has been evaluated by semiquantitative or morphometric techniques.[8]

Most of the transplant centers in developed countries are routinely doing preimplantation biopsy. In developing countries, few transplant centers have started doing preimplantation biopsies [Table 1].

Table 1: Pros and cons of preimplantation renal biopsy in the Indian context

In the United States, biopsies are done in 50% of the kidneys procured for transplantation; graft biopsies are done in 85% of ECD kidneys.[9] About 40% of deceased donor kidneys and 45% of ECD kidneys were discarded.[10]

There has been growing concern on whether biopsy findings inappropriately caused discard of at least some kidneys that are otherwise suitable for transplantation.

Two types of biopsies are done during procurement of kidney transplant, which are as follows:

Procurement biopsy (also called preimplantation biopsy, harvest, or donor biopsy) is performed at the time of organ procurement, usually frozen sections which can have limited correlations with formalin-fixed, paraffin-embedded sections for glomerulosclerosis and advanced interstitial fibrosis

Implantation biopsy is performed at the kidney transplantation, either before or after anastomosis. It utilizes formalin-fixed, paraffin-embedded sections requiring hours of preparations. However, it has limited value in deciding acceptance of the kidney for transplantation.

KDPI is mapped from KDRI, although its predictive power is modest. The Organ Procurement and Transplantation Network (OPTN) recommends preimplantation biopsy for all the kidneys with KDPI more than 85% (OPTN policy 2.12A).[10]

Preimplantation biopsies will provide insight about the [Table 2] suitability of the organ for transplantation. It helps to estimate its projected survival and in deciding whether the organ should be transplanted or discarded. There is no consensus on either the prognostic significance of biopsy findings in this setting or even on reporting standards for pretransplant kidney biopsies. This may lead to inconsistent interpretation, diminishing the diagnostic value of biopsy resulting in inappropriate discard of a potentially viable kidney.

In Maryland Aggregate Pathology Index,[15] they assessed the following parameters for glomerular pathology: percentage of glomerulosclerosis, diameter of glomerulus in micron meter, presence of any periglomerular fibrosis, and the fraction of arterial wall to lumen ratio; for vascular pathology: presence of any arteriolar hyalinosis; and for interstitial pathology: presence of cumulative fibrosis and any scar.

In the semiquantitative scale for the renal biopsy score according to the Karpinski classification, glomerular score depending on the percentage globally sclerosed glomeruli, tubular score depending on the percentage of tubules affected, interstitial score depending on the percentage of cortical parenchyma replaced by fibrous connective tissue and vascular score based on the arteriolar narrowing for hyaline arteriolosclerosis and arterial sclerosis for intimal fibrous thickening, and fibroplasias comparing the degree of increase in wall thickness with the diameter of the lumen were used. The kidneys with a score of 3 in any of the vascular, glomerular, interstitial, and tubular sections of the Karpinski[16] score were not allocated as single kidney transplant (SKT). Diabetic donors with a score of Karpinski of 4 or 5 were not allocated as SKT.

In renal transplant, procurement biopsy is obtained to decide whether the kidneys are ideal for transplantation.

There are two types of preimplantation biopsies as follows:

Open wedge biopsy includes mostly outer cortex overestimates glomerulosclerosis. The chances of damaging the large blood vessels are less

Wedge biopsy damages the large blood vessels less compared to needle biopsy but underestimates the severity of vascular lesions and overestimates the severity of glomerulosclerosis. Needle biopsy techniques are considered favorable by many as it has increased sensitivity in estimating cortical lesions.

Banff preimplantation biopsy working group[17] developed consensus for the interpretation of preimplantation kidney biopsies. They used 12 parameters – number of glomeruli, number of globally sclerosed, percentage of globally sclerosed, interstitial inflammation, total includes scarred areas, interstitial fibrosis, tubular atrophy, arterial intimal fibrosis, arteriolar hyalinosis, glomerular thrombi, acute tubular injury, and inflammation in nonscarred areas (Banff i score). The intraclass correlations (ICCs) were used to measure the reproducibility between pathologists. An ICC of more than 0.5 was considered to represent adequate agreement. The parameters were compared between frozen and defrozen paraffin biopsies.

ICC was excellent in frozen core sections for only number of glomeruli, but defrozen paraffin core sections showed better ICC for the number of glomeruli, number of globally sclerosed glomeruli, and arterial intimal fibrosis. All other histological parameters had fair or poor correlation including interstitial fibrosis and tubular atrophy. On wedge biopsies, defrozen paraffin biopsy ICC was excellent for number of globally sclerosed glomeruli and interstitial inflammation and fair correlation for remaining parameters. Frozen wedge biopsies showed greater concordance for number of glomeruli, number of globally sclerosed glomeruli, and interstitial inflammation when compared to frozen core sections. Comparing frozen sections of wedge kidney biopsies with corresponding paraffin sections showed comparable reproducibility, except frozen evaluation of arteriolar hyalinosis which showed poor correlation compared with fair correlation using paraffin sections. Evaluation of number of arteries, arterial intimal fibrosis, arteriolar hyalinosis, and tubular injury was comparable but showed poor concordance between wedge and frozen section biopsies.

The significance of pretransplant biopsies was that the inclusion criteria of most of the studies done on the utility of pretransplant biopsies were all transplants done in their centers and exclusion criteria were biopsies of inadequate tissue samples.

In a study by Gaber et al.,[6] glomerulosclerosis threshold of 20% was associated with adverse outcomes and this has been subsequently become a widely used threshold. Majority of studies showed no association between glomerulosclerosis and graft outcomes. DGF was not found to be associated with glomerulosclerosis in any of the studies expect that by Gaber et al.

Vascular injury was reported as arteriolar hyalinosis (ah) or arteriosclerosis (as). Majority of the studies showed that vascular injury was associated with poor graft outcomes. Tubular damage was reported as chronic interstitial fibrosis, tubular atrophy, and/or acute tubular necrosis. Most of the studies found that tubulointerstitial damage is not associated with graft failure.

They concluded that there was no consistent association between donor graft biopsy findings and posttransplant outcomes.

Although there are no guidelines on absolute indications for preimplantation biopsy at present, the indications of preimplantation renal biopsy are as follows:

To decide about organ to be accepted or discarded and quality of organs. As Gaber et al.[6] reported that >20% glomerulosclerosis on biopsy was associated with reduced graft survival

Preimplantation biopsies done as zero-hour biopsy can be taken as protocol biopsy, if it is done using the same techniques used in processing posttransplant biopsy.

Discussion

The clinical context of doing renal biopsy is very important in situ ations of disseminated intravascular coagulation. Donor biopsies performed need evaluation for the extent of microvascular injury. Organs with diffuse and extensive glomerular thrombosis should be discarded. In the presence of normal or minimal elevation of donor serum creatinine, mere presence of scattered capillary thrombi is not a contraindication of renal transplantation.[19] The issue of rapid protocols for formalin fixation and paraffin embedding, now technically much improved and increasingly adopted in clinical practice needs to be evaluated. Digitally scanned slides can be accessed remotely from various centers.

Novel ultrarapid processing protocols may be useful to reduce the time required to obtain formalin-fixed sections of preimplantation kidney biopsies.

The quality of procurement biopsies could be maximized using needle rather than wedge biopsies, obtaining three adequate cores, requiring at least 25 glomeruli is considered adequate. Replacing frozen tissue with rapid paraffin embedding, whenever possible, using a standardized reporting form to encourage adequate reporting of all important biopsy elements.

Training of general pathologist to read donor biopsies using consistent criteria should be pursued.

Conclusions

In future, new and/or improved techniques of biopsy interpretation can improve posttransplant outcomes. It is advisable to include tissue cores from all compartments. Prospective observational studies with adequate statistical power are needed to determine whether biopsies can predict transplant outcomes.

Till randomized control trials determining the advantages and disadvantages of preimplantation biopsies are established, routine use of preimplantation biopsy cannot be recommended at all centers.